Authors:Yakymovych I; Yakymovych M, Heldin C.First page: 3Abstract: Transforming growth factor β (TGFβ) family members signal via heterotetrameric complexes of type I (TβRI) and type II (TβRII) dual specificity kinase receptors. The availability of the receptors on the cell surface is controlled by several mechanisms. Newly synthesized TβRI and TβRII are delivered from the Golgi apparatus to the cell surface via separate routes. On the cell surface, TGFβ receptors are distributed between different microdomains of the plasma membrane and can be internalized via clathrin- and caveolae-mediated endocytic mechanisms. Although receptor endocytosis is not essential for TGFβ signaling, localization of the activated receptor complexes on the early endosomes promotes TGFβ-induced Smad activation. Caveolae-mediated endocytosis, which is widely regarded as a mechanism that facilitates the degradation of TGFβ receptors, has been shown to be required for TGFβ signaling via non-Smad pathways. The importance of proper control of TGFβ receptor intracellular trafficking is emphasized by clinical data, as mislocalization of receptors has been described in connection with several human diseases. Thus, control of intracellular trafficking of the TGFβ receptors together with the regulation of their expression, posttranslational modifications and down-regulation, ensure proper regulation of TGFβ signaling.PubDate: Sat, 25 Nov 2017 00:00:00 GMTDOI: 10.1093/abbs/gmx119

Authors:Nickel J; ten Dijke P, Mueller T.First page: 12Abstract: Transforming growth factor-β (TGF-β) family members, which include TGF-βs, activins and bone morphogenetic proteins, are pleiotropic cytokines that elicit cell type-specific effects in a highly context-dependent manner in many different tissues. These secreted protein ligands signal via single-transmembrane Type I and Type II serine/threonine kinase receptors and intracellular SMAD transcription factors. Deregulation in signaling has been implicated in a broad array of diseases, and implicate the need for intricate fine tuning in cellular signaling responses. One important emerging mechanism by which TGF-β family receptor signaling intensity, duration, specificity and diversity are regulated and/or mediated is through cell surface co-receptors. Here, we provide an overview of the co-receptors that have been identified for TGF-β family members. While some appear to be specific to TGF-β family members, others are shared with other pathways and provide possible ways for signal integration. This review focuses on novel functions of TGF-β family co-receptors, which continue to be discovered.PubDate: Wed, 27 Dec 2017 00:00:00 GMTDOI: 10.1093/abbs/gmx126

Authors:Yan X; Xiong X, Chen Y.First page: 37Abstract: Transforming growth factor beta (TGF-β) is a multi-functional polypeptide that plays a critical role in regulating a broad range of cellular functions and physiological processes. Signaling is initiated when TGF-β ligands bind to two types of cell membrane receptors with intrinsic Ser/Thr kinase activity and transmitted by the intracellular Smad proteins, which act as transcription factors to regulate gene expression in the nucleus. Although it is relatively simple and straight-forward, this TGF-β/Smad pathway is regulated by various feedback loops at different levels, including the ligand, the receptor, Smads and transcription, and is thus fine-tuned in terms of signaling robustness, duration, specificity, and plasticity. The precise control gives rise to versatile and context-dependent pathophysiological functions. In this review, we firstly give an overview of TGF-β signaling, and then discuss how each step of TGF-β signaling is finely controlled by distinct modes of feedback mechanisms, involving both protein regulators and miRNAs.PubDate: Fri, 08 Dec 2017 00:00:00 GMTDOI: 10.1093/abbs/gmx129

Authors:Zhao R; Li N, Xu J, et al.First page: 51Abstract: TGF-β/Smad signaling pathway triggers diverse cellular responses among different cell types and environmental conditions. Quantitative analysis of protein-protein interactions involved in TGF-β/Smad signaling is demanded for understanding the molecular mechanism of this signaling pathway. Live-cell single-molecule microcopy with high spatiotemporal resolution is a new tool to monitor key molecular events in a real-time manner. In this review, we mainly presented the recent work on the quantitative characterization of TGF-β/Smad signaling proteins by single-molecule method, and showed how it enabled us to obtain new insights about this canonical signaling process.PubDate: Tue, 28 Nov 2017 00:00:00 GMTDOI: 10.1093/abbs/gmx121

Authors:Bai J Xi Q.First page: 60Abstract: The transforming growth factor beta (TGF-β) family of ligands plays major roles in embryonic development, tissue homeostasis, adult immunity, and wound repair. Dysregulation of TGF-β signaling pathway leads to severe diseases. Its key components have been revealed over the past two decades. This family of cytokines acts by activating receptor activated SMAD (R-SMAD) transcription factors, which in turn modulate the expression of specific sets of target genes. Cells of a multicellular organism have the same genetic information, yet they show structural and functional differences owing to differential expression of their genes. Studies have demonstrated that epigenetic regulation, an integral part of the TGF-β signaling, enables cells to sense and respond to TGF-β signaling in a cell context-dependent manner. R-SMAD, as the central transcription factor of TGF-β signaling, can recruit various epigenetic regulators to shape the transcriptome. In this review, we focus on epigenetic regulatory mechanisms in the TGF-β signaling during mammalian development and diseases and discuss the central role of the interaction between R-SMAD and various epigenetic regulators in this epigenetic regulation. The crosstalk between TGF-β signaling and the epigenome could serve as a versatile fine-tuning mechanism for transcriptional regulation during embryonic development and progression of diseases, particularly cancer.PubDate: Tue, 28 Nov 2017 00:00:00 GMTDOI: 10.1093/abbs/gmx122

Authors:Liu C; Peng G, Jing N.First page: 68Abstract: TGF-β superfamily signaling pathways essentially contribute to the broad spectrum of early developmental events including embryonic patterning, cell fate determination and dynamic movements. In this review, we first introduced some key developmental processes that require TGF-β signaling to show the fundamental importance of these pathways. Then we discuss how their activities are regulated, and new findings about how the TGF-β superfamily ligands bind to the chromatin to regulate transcription during embryo development.PubDate: Tue, 28 Nov 2017 00:00:00 GMTDOI: 10.1093/abbs/gmx120

Authors:Wei S; Wang Q.First page: 74Abstract: One of the most important events during vertebrate embryogenesis is the formation or specification of the three germ layers, endoderm, mesoderm, and ectoderm. After a series of rapid cleavages, embryos form the mesendoderm and ectoderm during late blastulation and early gastrulation. The mesendoderm then further differentiates into the mesoderm and endoderm. Nodal, a member of the transforming growth factor β (TGF-β) superfamily, plays a pivotal role in mesendoderm formation by regulating the expression of a number of critical transcription factors, including Mix-like, GATA, Sox, and Fox. Because the Nodal signal transduction pathway is well-characterized, increasing effort has been made to delineate the spatiotemporal modulation of Nodal signaling during embryonic development. In this review, we summarize the recent progress delineating molecular regulation of Nodal signal intensity and duration during mesendoderm formation.PubDate: Fri, 01 Dec 2017 00:00:00 GMTDOI: 10.1093/abbs/gmx128

Authors:Song J; Shi W.First page: 91Abstract: TGF-β’s multipotent cellular effects and their relations are critical for TGF-β’s pathophysiological functions. However, these effects may appear to be paradoxical in understanding TGF-β’s functions. Apoptosis and epithelial–mesenchymal transition (EMT) are two fundamental events that are deeply linked to various physiological and disease-related processes. These two major cellular fates are subtly regulated and can be potently stimulated by TGF-β, which profoundly contribute to the biological roles of TGF-β. Moreover, these two events are also indirectly and directly correlated with TGF-β-mediated growth inhibition and are relevant to the current understanding of the roles of TGF-β in tumorigenesis and cancer progression. Although TGF-β-induced apoptosis and EMT can be singly independent cellular events, they can also be mutually exclusive but interrelated concomitant events in various cases. Thus, the modulation of apoptosis and EMT is essential for the seemingly paradoxical functions of TGF-β. However, the concomitant effect of TGF-β on apoptosis and EMT, the balance and regulated alterations of them are still been ignored or underestimated. This review focuses on the TGF-β-induced concomitant apoptosis and EMT. We aim to provide an insight in understanding their significance, balance, and modulation in TGF-β-mediated biological functions.PubDate: Sat, 21 Oct 2017 00:00:00 GMTDOI: 10.1093/abbs/gmx117

Authors:Wu F; Weigel K, Zhou H, et al.First page: 98Abstract: Transforming growth factor β (TGF-β) signaling either promotes or inhibits tumor formation and/or progression of many cancer types including squamous cell carcinoma (SCC). Canonical TGF-β signaling is mediated by a number of downstream proteins including Smad family proteins. Alterations in either TGF-β or Smad signaling can impact cancer. For instance, defects in TGF-β type I and type II receptors (TGF-βRI and TGF-βRII) and in Smad2/3/4 could promote tumor development. Conversely, increased TGF-β1 and activated TGF-βRI and Smad3 have all been shown to have tumor-promoting effects in experimental systems of human and mouse SCCs. Among TGF-β/Smad signaling, only TGF-βRII or Smad4 deletion in mouse epithelium causes spontaneous SCC in the mouse model, highlighting the critical roles of TGF-βRII and Smad4 in tumor suppression. Herein, we review the dual roles of the TGF-β/Smad signaling pathway and related mechanisms in SCC, highlighting the potential benefits and challenges of TGF-β/Smad-targeted therapies.PubDate: Fri, 01 Dec 2017 00:00:00 GMTDOI: 10.1093/abbs/gmx127

Authors:Kashima R; Hata A.First page: 106Abstract: The TGF-β superfamily signaling is involved in a variety of biological processes during embryogenesis and in adult tissue homeostasis. Faulty regulation of the signaling pathway that transduces the TGF-β superfamily signals accordingly leads to a number of ailments, such as cancer and cardiovascular, metabolic, urinary, intestinal, skeletal, and immune diseases. In recent years, a number of studies have elucidated the essential roles of TGF-βs and BMPs during neuronal development in the maintenance of appropriate innervation and neuronal activity. The new advancement implicates significant roles of the aberrant TGF-β superfamily signaling in the pathogenesis of neurological disorders. In this review, we compile a number of reports implicating the deregulation of TGF-β/BMP signaling pathways in the pathogenesis of cognitive and neurodegenerative disorders in animal models and patients. We apologize in advance that the review falls short of providing details of the role of TGF-β/BMP signaling or mechanisms underlying the pathogenesis of neurological disorders. The goal of this article is to reveal a gap in our knowledge regarding the association between TGF-β/BMP signaling pathways and neuronal tissue homeostasis and development and facilitate the research with a potential to develop new therapies for neurological ailments by modulating the pathways.PubDate: Tue, 28 Nov 2017 00:00:00 GMTDOI: 10.1093/abbs/gmx124

Authors:Xie F; Ling L, van Dam H, et al.First page: 121Abstract: The transforming growth factor (TGF)-β signaling events are well known to control diverse processes and numerous responses, such as cell proliferation, differentiation, apoptosis, and migration. TGF-β signaling plays context-dependent roles in cancer: in pre-malignant cells TGF-β primarily functions as a tumor suppressor, while in the later stages of cancer TGF-β signaling promotes invasion and metastasis. Recent studies have also suggested that the cross-talk between TGF-β signaling and other signaling pathways, such as Hippo, Wnt, EGFR/RAS, and PI3K/AKT pathways, may substantially contribute to our current understanding of TGF-β signaling and cancer. As a result of the wide-ranging effects of TGF-β, blockade of TGF-β and its downstream signaling components provides multiple therapeutic opportunities. Therefore, the outlook for anti-TGF-β signaling therapy for numerous diseases appears bright and will provide valuable information and thinking on the drug molecular design. In this review, we focus on recent insights into the regulation of TGF-β signaling in cancer metastasis which may contribute to the development of novel cancer-targeting therapies.PubDate: Tue, 28 Nov 2017 00:00:00 GMTDOI: 10.1093/abbs/gmx123